Energy-producing metabolic pathways may be critically inhibited during severe ischemia by factors other than reduced oxygen availability. Under less severe conditions, function of certain pathways are retained at near normal capacity. Glucose metabolism may be accelerated and oxidative phosphorylation reactions continue to produce ATP at a rate proportional to the oxygen availability. The overally goal of our proposal is to investigate the limits and mechanisms of metabolic adaptations that occur in ischemic myocardium and to exploit those reactions that are preserved. Studies are planned which will enhance those pathways likely to result in increased energy production. Pyruvate with and without the added effects of dichloroacetate, acetate, acetoacetate, and beta-hydroxybutyrate will be used to determine the best substrate for efficient utilization of the residual oxidative capacity in ischemic hearts. Studies to evaluate methods to delay buildup of inhibitory metabolic products are also planned. Several compounds have been identified as potential inhibitors of energy production in ischemic tissue. Derivatives of fatty acid metabolism, in particular fatty acyl CoA, have been suspect in the regard by disrupting membrane translocation of adenine nucleotides and perhaps by altering the normal yield of ATP from each oxygen molecule used. To prevent buildup of this compound, several agents including beta-bromo long-chain fatty acids, natural and unnatural isomers of carnitine, and competitive binders of CoASH (pyruvate, acetate, and ketone bodies) will be supplied. The present project will use two swine heart preparations to selectively evaluate metabolic and mechanical functions in globally and regionally ischemic myocardium. Both have capabilities of controlling total or regional coronary blood flow, measuring various aspects of hemodynamic and regional myocardial motion, and determining myocardial metabolism from samplings of the coronary perfusate and from tissue biopsies of several cardiac metabolites. The health-related significance of these studies will be to focus on one metabolic aspect of ischemic heart disease in hope of finding a promising avenue to protect ischemic heart from irreversible damage.